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Electronic Resource

Kennedy's Disease (1999)

Ellerby, Lisa M. ; Hackam, Abigail S. ; Propp, Stephanie S. ; [et al.]

Oxford UK : Blackwell Science Ltd.

Journal of neurochemistry 72 (1999), S. 0

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ISSN: 1471-4159

Source: Blackwell Publishing Journal Backfiles 1879-2005

Topics: Medicine

Notes: Abstract : X-linked spinal and bulbar muscular atrophy (SBMA),Kennedy's disease, is a degenerative disease of the motor neurons that isassociated with an increase in the number of CAG repeats encoding apolyglutamine stretch within the androgen receptor (AR). Recent work hasdemonstrated that the gene products associated with open reading frame tripletrepeat expansions may be substrates for the cysteine protease cell deathexecutioners, the caspases. However, the role that caspase cleavage plays inthe cytotoxicity associated with expression of the disease-associated allelesis unknown. Here, we report the first conclusive evidence that caspasecleavage is a critical step in cytotoxicity ; the expression of the AR with anexpanded polyglutamine stretch enhances its ability to induce apoptosis whencompared with the normal AR. The AR is cleaved by a caspase-3 subfamilyprotease at Asp146, and this cleavage is increased duringapoptosis. Cleavage of the AR at Asp146 is critical for theinduction of apoptosis by AR, as mutation of the cleavage site blocks theability of the AR to induce cell death. Further, mutation of the caspasecleavage site at Asp146 blocks the ability of the SBMA AR to form perinuclear aggregates. These studies define a fundamental role for caspase cleavage in the induction of neural cell death by proteins displaying expanded polyglutamine tracts, and therefore suggest a strategy that may be useful to treat neurodegenrative diseases associated with polyglutamine repeat expansions.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1046/j.1471-4159.1999.0720185.x

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Codon-usage variants in the polymorphic (GGN) n trinucleotide repeat of the human androgen receptor gene (1997)

Lumbroso, Rose ; Beitel, Lenore K. ; Vasiliou, D. Marie ; [et al.]

Springer

Human genetics 〈Berlin〉 101 (1997), S. 43-46

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ISSN: 1432-1203

Source: Springer Online Journal Archives 1860-2000

Topics: Biology , Medicine

Notes: Abstract The human androgen receptor gene (hAR) has a long, polymorphic trinucleotide (GGN; glycine) n repeat in the 3′ portion of its first exon, with n = 10–31. Owing to technical difficulties that have precluded routine sequencing of this region, it is widely unknown that N represents T, G or C, and that the usual sense codon sequence of the GGN tract is (GGT)3GGG(GGT)2(GGC)4–25. Furthermore, on 4 of 61 X chromosomes, we observed that the internal GGT sequence was present three or four times instead of twice. Strikingly, each of the three alleles with an internal (GGT)3, and only these three, also had a (GGC)20 repeat. The size or composition of a (GGN) n repeat was not correlated with the length of the accompanying (CAG) n CAA repeat in the 5′ portion of exon one. Hence, codon-usage variants of the GGN tract may be used to seek associations with particular diseases, as diagnostic aids in families with androgen insensitivity whose AR mutations have not yet been identified, or as internal controls for observations on intergenerational contractions or expansions of the (CAG) n CAA tract in a given hAR allele.